Assessing the Dual Activity of a Chalcone–Phthalocyanine Conjugate: Design, Synthesis, and Antivascular and Photodynamic Properties

Abstract

Photodynamic therapy (PDT) and vascular-disrupting agents (VDA) each have their advantages in the treatment of solid tumors, but also present drawbacks. In PDT, hypoxia at the center of the tumor limits conversion of molecular oxygen into singlet oxygen, while VDAs are deficient at affecting the rim of the tumor. A phthalocyanine-chalcone conjugate combining the VDA properties of chalcones with the PDT properties of phthalocyanines was designed to address these deficiencies. Its vascular targeting, photophysical, photochemical, photodynamic activities are reported herein.

Chalcone: A Privileged Structure in Medicinal Chemistry

“…It has been reported that chalcones with VDA properties can covalently bind to phthalocyanine with PDT properties to achieve phthalocyanine–chalcone conjugates (Figure 21, 124 and 125 ). 372,373 Compound 124 was first designed and obtained by the condensation of tetrahydroxylated nonperipherally substituted Zn(II) phthalocyanine and isocyanate chalcone. 372 Compound 125 has been designed to address the deficiency of being too hydrophobic for biological explorations.…”

“…372 Compound 125 has been designed to address the deficiency of being too hydrophobic for biological explorations. 373 This monochalcone–phthalocyanine has been synthesized and characterized to show an improved vascular targeting activity due to the incorporation of a cleavable bond (highlighted in red) selectively releasing chalcone at the tumor tissue and the capability to generate singlet oxygen. This example provides a promising strategy for the treatment of solid tumors by combining a photosensitizer and a VDA into one molecule.…”

The synthesis of an octasubstituted monohydroxylated phthalocyanine designed to investigate the effect of the presence of active moieties

“…Grafting active moieties onto phthalocyanines allows us to combine two properties and to obtain dual effects for biomedical applications. The photosensitizing ability of phthalocyanines used in photodynamic therapy has been combined with the imaging properties of Gd-DOTA, 6 to the antivascular effect of chalcones, 7 to the tumour targeting effect of antibodies 8 or several active moieties such as carbohydrates, 9 folic acid. 10 Phthalocyanines can be functionalized for other purposes as well: grafting onto polymers 11 and nanoparticles, 12 and conjugation with energy-transfer or electron-transfer units, among others.…”

Bisphthalonitrile with a Disulfide-Based Linker and its Dimethylene Analogue: Comparative Structural Insights

“…It is known indeed that dimeric phthalocyanines are more aggregated than monomeric ones [16][17][18], inducing a self-quenching of their photoproperties. This prompted us to design dimeric phthalocyanines linked by a disulfide-based linker.…”